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Ceftriaxone-Induced Hemolytic Anemia With Severe Renal Failure: A Case Report and Review of Literature
Ceftriaxone-Induced Hemolytic Anemia With Severe Renal Failure: A Case Report and Review of Literature
Abstract
Background: Drug induced immune hemolytic anemia (DIIHA) is a rare complication and often underdiagnosed.
DIIHA is frequently associated with a bad outcome, including organ failure and even death. For the last decades,
ceftriaxone has been one of the most common drugs causing DIIHA, and ceftriaxone-induced immune hemolytic
anemia (IHA) has especially been reported to cause severe complications and fatal outcomes.
Case presentation: A 76-year-old male patient was treated with ceftriaxone for cholangitis. Short time after
antibiotic exposure the patient was referred to intensive care unit due to cardiopulmonary instability. Hemolysis was
observed on laboratory testing and the patient developed severe renal failure with a need for hemodialysis for 2 weeks.
Medical history revealed that the patient had been previously exposed to ceftriaxone less than 3 weeks before with
subsequent hemolytic reaction. Further causes for hemolytic anemia were excluded and drug-induced immune
hemolytic (DIIHA) anemia to ceftriaxone could be confirmed.
Conclusions: The case demonstrates the severity of ceftriaxone-induced immune hemolytic anemia, a rare, but
immediately life-threatening condition of a frequently used antibiotic in clinical practice. Early and correct diagnosis of
DIIHA is crucial, as immediate withdrawal of the causative drug is essential for the patient prognosis. Thus, awareness for
this complication must be raised among treating physicians.
Keywords: Drug-induced immune hemolytic anemia, Ceftriaxone, Hemolysis
large-volume paracentesis without signs of spontaneous depicted in Fig. 1). Furthermore, the patient subsequently
bacterial peritonitis or malignancy. On the second day developed a severe acute kidney failure with uremia (peak
after hospitalization, an esophagogastroduodenoscopy was creatinine 6.29 mg/dl (556.04 μmol/l), urea 192.3 mg/dl
performed to screen for esophageal varices. After the (32.11 mmol/l)) and intermittent hemodialysis was neces-
intervention, the patient developed fever and chills. Chol- sary for 14 days. A kidney biopsy was performed and
angitis was suspected due to biliodigestive anastomosis, showed a severe acute tubular damage fitting with
increase of cholestasis parameters and an antibiotic treat- shock-induced injury and/or tubular-toxic effects of free
ment with ceftriaxone was started the same day (dose 4 g hemoglobin/hemin.
intravenously). Immediately after drug application the pa- The massive hemolytic reaction came suddenly and
tient complained about nausea, vomited and developed was unexpected. After exclusion of hematological co-
dyspnea, confusion and a positive shock index (systolic morbidities, a detailed patient history with current drug
RR < 100 mmHg, cardiac frequency 140 /min). The pa- exposure was performed. Before admission to our de-
tient was referred to our intensive care unit and the anti- partment the patient had been hospitalized in our surgi-
biotic regime was escalated to piperacillin/tazobactam and cal department due to pneumothorax after pacemaker
ciprofloxacin for sepsis therapy. The patient received no implantation. During this hospitalisation (< 3 weeks be-
further dose of ceftriaxone. Laboratory analysis about 1 h fore the current admission) the patient had already been
after application of ceftriaxone showed first signs of treated with ceftriaxone for at least 6 days and had
hemolysis with an elevated lactate dehydrogenase (LDH) already developed mild hemolysis in laboratory analysis
(1,116 U/L (18.6 μkat/l); baseline 290 U/L (4.83 μkat/l)) without further consequences at that time. Further de-
and a decrease in hemoglobin (6.4 g/dl (3.97 mmol/l), tailed diagnostic showed a positive Coombs’ direct anti-
baseline 8.5 g/dl (5.28 mmol/l)). Coagulation parameters globulin test (DAT) for immunoglobulin M (IgM),
were significantly disturbed indicating DIC with an inter- immunoglobulin G (IgG) and complement factor C3d.
national normalized ratio (INR) of 3.31 (baseline 1.29), fi- On Naranjo Scale, a probability scale for adverse drug
brinogen not measurable, thrombocytopenia down to reactions, the patient would have reached a value of 9
56,000/μl (baseline 203,000/μl). During the next days, the points (maximal score 13 points, with values ≥9 points
patient developed an increase in leukocytes (up to 23,000/ indicating a definite adverse drug reaction) [10]. The
μL) and in infection parameters (peak C-reactive protein suspected DIIHA was proven by reference laboratory
(CRP) 9.35 mg/dl (890.48 nmol/l), peak procalcitonin analysis (Institute of Transfusion Medicine, Charité,
(PCT) 134 μg/l). Additionally, hemolysis aggravated with a Berlin), confirming the presence of a strongly agglutinat-
nadir hemoglobin of 4.8 g/dl (2.98 mmol/l), an elevated ing ceftriaxone-dependent antibody (Fig. 2).
LDH up to 1,734 U/L (28.9 μkat/l) and suppressed hapto- The patient’s situation stabilized with decrease of
globin < 0.1 g/l. (course of laboratory parameters is hemolysis parameters, stable hemoglobin levels and
nadir hemoglobin < 8 g/dl (4.96 mmol/l) in 9 cases and drug-independent antibodies [19]. In a review of 37
in 3 of these cases the nadir was even below 3 g/dl cases of ceftriaxone-induced IHA a weaker and self-lim-
1.86 mmol/l) [6]. Arndt et al. analyzed 25 cases of iting hemolytic episode associated with earlier
ceftriaxone-induced IHA including 17 children [2]. ceftriaxone-application could be observed in 32% of
Ceftriaxone-induced IHA seems to be more frequent these patients [7], underlining the assumption that espe-
and more severe in children [2, 3, 6, 7, 11]. In the series cially secondary immune responses are responsible for
of Arndt et al., 16 patients had a nadir hemoglobin < severe DIIHA in general. A massive drop in hemoglobin
5 g/dl (3.1 mmol/l), and among these 16 patients were levels in these patients led to severe complications such
13 children. In three patients, the nadir was even < 1 g/ as shock, circulatory arrest, organ ischemia, dissemi-
dl (0.62 mmol/l) and all of them were children [2]. Chil- nated intravascular coagulation (DIC), acute respiratory
dren suffering from serious underlying diseases like HIV distress syndrome (ARDS) in 27 patients and 30% of the
infection or sickle cell disease seem to be predisposed to patients died [7]. Surprisingly, drug-dependent anti-
develop ceftriaxone-induced IHA [17], and in sickle cell bodies were detected also in healthy persons (blood do-
disease ceftriaxone-dependent antibodies may also lead nors/random patients) in much lower titers than in
to fatal sickle cell-crisis [18]. In our patient, the second patients who developed DIIHA. This interesting finding
hemolytic episode was much worse than the first one. might be associated with antibiotic use in industrial ani-
This finding is typical for DIIHA [7, 11] and is due to a mal breeding [4, 5, 13], but the clinical relevance of this
secondary immune response. The immune system of pa- phenomenon is still unknown. However, one could
tients receiving a drug for the first time in their life speculate that these persons might be predestinated to
needs some days to produce drug-dependent or also develop clinically relevant antibody-titers and
Leicht et al. BMC Pharmacology and Toxicology (2018) 19:67 Page 5 of 7
subsequent hemolysis after receiving therapeutic doses responsible drug is the most important therapeutic
of the respective antibiotic [3]. The high prevalence of measure in order to stop the immunologic stimulation.
acute renal failure in patients with DIIHA in general is Additionally, in cases of drug-independent antibodies,
not only because of hypoperfusion/ischemia due to intravenous immunoglobulins (IVIG) can be given, if
hemoglobin decrease and shock, but especially because there is evidence of intravascular hemolysis, like in treat-
of the nephrotoxicity of free hemoglobin and hemin ment of WAIHA [27]. Administration of high-dose IVIG
[20]. Beyond their nephrotoxicity there are other proin- has been successfully used in a child with severe
flammatory effects of free hemoglobin and hemin that ceftriaxone-induced IHA and a nadir hemoglobin of
have to be considered in patients with DIIHA and might 2.2 g/dl (1.37 mmol/l) [24]. However, the question re-
probably aggravate the clinical course of the patients mains open whether the positive outcome of the patient
(reviewed in [21]). was due to IVIG therapy or due to cessation of ceftriax-
It has been noticed that ceftriaxone causes more severe one. In some cases, plasmapheresis/plasma exchange has
clinical courses and more fatal outcomes than other drugs been used for treating DIIHA [3, 7, 8]. It could be specu-
responsible for DIIHA [3, 6]. Ceftriaxone has been shown lated that removing drug-induced antibodies from the
to induce primarily antibodies of IgM-type with accom- patient’s serum actively via plasmapheresis could be
panying IgG-antibodies [1–3]. IgM-type drug-dependent helpful in patients with “drug adsorption-type” DIIHA or
antibodies lead to binding and activation of complement, with severe renal failure, where the causative drug is not
which results in intravascular hemolysis. In fact, intravas- eliminated within its normal half-time and might there-
cular hemolysis through complement-mediated lysis is a fore trigger a prolonged hemolysis as well as an intensi-
hallmark of “immune-complex-type” DIIHA [1, 11]. In fied immunologic stimulation.
line with this, Coombs’ direct antiglobulin test (DCT) in As DIIHA of “immune complex-type” is due to
ceftriaxone-induced IHA is usually positive for C3 and, in complement-mediated intravascular hemolysis, one is
some cases, also for IgG [1–3, 22–24]. However, negative tempted to speculate that a therapy with eculizumab, a
DCT has also been described in ceftriaxone-induced IHA, complement inhibitor which hinders the formation of the
probably because of massive hemolysis and therefore lack “membrane attack complex”, could be helpful in these pa-
of intact complement−/antibody-loaded erythrocytes in tients. Eculizumab is successfully used in paroxysmal noc-
this special case [25]. In our patient a positive DCT was turnal hemoglobinuria and (atypical) hemolytic uremic
observed for IgM, IgG and C3d. syndrome, and there have also been reports of its use in
Most importantly, if DIIHA is suspected, the suspi- autoimmune hemolytic anemia [28, 29]. To our know-
cious drug must be stopped immediately. Discontinu- ledge, there is no report of the use of eculizumab in a pa-
ation of the drug is the most important treatment tient with DIIHA to date. However, complement
measure concerning the patient’s outcome. In children inhibitors might be an effective therapeutic option espe-
with ceftriaxone-induced IHA, 8 of 9 patients, whose cially in cases with severe intravascular hemolysis [30].
ceftriaxone therapy was stopped immediately, survived. After the diagnosis of DIIHA, there is an absolute
In contrast, children without cessation of ceftriaxone contraindication for re-exposure of the responsible drug
treatment after diagnosis had a mortality of 50% [8]. for the patient’s lifetime. The application of drugs of the
DIIHA patients should be admitted to an intensive care same substance class should be considered very care-
unit to provide optimal supportive care and if required fully, as there could be interactions of the drug-depend-
circulatory support. Transfusion of red blood cells will ing antibody and these similar drugs. In case of
be done to the necessary amount. Recently, a case of ceftriaxone-dependent antibodies e.g., cross-reactivity
ceftriaxone-induced IHA was reported with a patient re- has been shown with cefotaxime [6, 11, 23], cefpodox-
fusing transfusions for religious reasons (Jehova’s wit- ime proxetil [23], with cefamandole [11] and with cefo-
ness). In this case the patient could be stabilized with perazone [11]. In addition, drug-dependent antibodies
daily application of erythropoietin, ferrous sulfate, folic are not necessarily directed against the drug itself, but
acid and vitamin B12 [26]. In many cases, patients are can also be directed against a drug metabolite or against
given steroids. However, there is no proven benefit and both the intact drug and its metabolite(s) [3, 19, 23],
therefore no recommendation for steroid therapy in which makes crossreactions to drugs of the same sub-
DIIHA, at least as far as drug-dependent antibodies are stance class even more probable.
involved [3, 11, 14]. In general, reports of successful use Antagonizing the toxic effects of free hemoglobin and
of steroids in DIIHA are usually confounded by the free hemin could be an effective therapeutic strategy in
withdrawal of the responsible drug at the same time [3, future to prevent renal failure. In animal models of
11]. In cases of drug-independent antibodies, which are hemolysis, the application of haptoglobin (binding free
autoantibodies, steroid therapy can be tried [3, 14], but hemoglobin) as well as of hemopexin (binding free he-
also in these cases, the immediate withdrawal of the min) has proven beneficial [31, 32], so maybe purified
Leicht et al. BMC Pharmacology and Toxicology (2018) 19:67 Page 6 of 7
haptoglobin or hemopexin might become effective thera- Received: 24 April 2018 Accepted: 10 October 2018
peutic agents for DIIHA one day.
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